Dipyridamole-thallium scintigraphy predicts perioperative and long-term survival after major vascular surgery

Dipyridamole-thallium scintigraphy predicts perioperative and long-term survival after major vascular surgery Bruce S. Cutler, M D , R o b e r t C. Hendel, M D , and Jeffrey A. Leppo,

MD,

Worcester, Mass. The purpose of this study was to evaluate the ability of dipyridamole-thallium scintigraphy to predict perioperative and late cardiac events after peripheral vascular operations. A total of 262 patients had dipyridamole-thallium scintigraphy before 87 infrainguinal reconstructions, 108 abdominal aortic aneurysm operations, and 67 aortobifemoral bypass grafts that were placed for occlusive disease. Follow-up extended to 5 years (mean, 31.1 months). Logistic regression analysis selected dipyridamole-thaUium scintigraphy redistribution as the best predictor of perioperative events. Fixed defects were not predictive. A Cox proportional hazards model for a variety of clinical risk factors and scan parameters identified fixed defects and a history of congestive heart failure as the strongest predictors of late cardiac events. The presence of greater than 1 or 2 fixed segments were the best predictors in patients with an abnormal scan; redistribution did not predict late events. The risk of combined perioperative or late cardiac events was 29% for infrainguinal, 19% for abdominal aortic aneurysm, and 7.5% for aortobifemoral operations. Life-table analysis showed that after a cluster of perioperative events that occurred primarily in patients with dipyridamole-thallium scintigraphy redistribution, most of the late cardiac morbidity and deaths occurred in patients with fixed defects. (J VAsc SUv,G 1992;15: 972-81.)

A number of previous studies have demonstrated the utility of preoperative dipyridamole-thallium scintigraphy (DTS) in predicting the cardiac risk of vascular surgery. Some authors have used the test routinely before all elective vascular operations, 17 whereas others have advocated its selective application only to patients with certain clinical markers for coronary artery disease (CAD). 8'9 Nearly all studies to date have focused attention on perioPerative cardiac morbidity and death. Despite the availability of dipyridamole-thallium testing for over a decade, surprisingly little attention has been devoted to the long-term cardiac prognosis of patients surviving vascular operations. The purpose of this study is to

From the Divisionsof Vascular Surgery(Dr. Cutler) and Nuclear Medicine (Drs. Hendel and Leppo) and the Department of Cardiology (Drs. Hendel and Leppo), the University of MassachusettsMedical School,Worcester. Presented at the EighteenthAnnualMeetingof the New England Society for Vascular Surgery, Quebec, Canada, Sept. 26-27, 1991. Reprint requests: Bruce S. Cutler, MD, Division of Vascular Surgery, Universityof MassachusettsMedicalSchool, 55 Lake Ave. NorTh, Worcester,MA 01655. 24/6[36657, 972

investigate the value of preoperative DTS to predict perioperative and late cardiac events. PATIENTS IN THE STUDY AND METHODS During a 5-year period ending in December 1990, 341 consecutive patients underwent routine screening for CAD with DTS before operations on the aorta or infralnguinal bypass at the University of Massachusetts Medical Center. On the basis of clinical parameters and scan results, 33 patients were treated conservatively without operations, and 46 others underwent one of the following alternative procedures: percutaneous angioplasty 11, sympathectomy 6, primary amputation 10, or an extraanatomic bypass graft 19. Patients who did not have an operation or who underwent an alternative procedure were excluded from further analysis to create three main groups of patients for ease of statistical evaluation. When the excluded patients were analyzed with the three main groups no difference existed in the factors that predicted early or late cardiac events. Two hundred sixty-two patients were available for retrospective evaluation of late outcome, corn-

Volume 15 Number 6 June 1992

posed of 87 infrainguinal reconstructions, 108 abdominal aortic aneurysm operations, and 67 aortobifemoral bypass grafts placed for treatment of aortoiliac occlusive disease. On the basis of a positive scan, 26 patients had cardiac catheterization. Nineteen of these went on to vascular surgery without further treatment of their cardiac disease. ~,The remaining seven had preliminary coronary artery bypass grafting before undergoing a vascular procedure. Neither the perioperative nor late event analysis was affected by the inclusion or exclusion of this subgroup. End points for the study were cardiac death and nonfatal myocardial infarction. The University of Minnesota criteria for myocardial infarction were used, which require a new Q wave 1 mm or greater ,~n electrocardiogram (ECG) or a myocardial band fraction of creatinine phosphokinase (CPK-MB) 5% or greater or both. Each subject was seen in consultation by a staff cardiologist who questioned the patient for symptoms and clinical risk factors of CAD and who interpreted the resting preoperative ECG. The presence of preoperative clinical risk factors for CAD and the finding of a Q wave on resting ECG were recorded. After operation, daily ECGs and serum cardiac enzyme levels were monitored for 72 hours. In addition, the patients' clinical course was followed by a cardiologist who also interpreted the ECG and enzyme abnormalities. All patients gave informed consent to a protocol approved by the University of Massachusetts Committee on Human Subjects before undergoing DTS. Baseline ECG and blood pressure measurements were obtained before, during, and after intravenous dipyridamole (Boehringher Ingleheim, Corp., Ridgefield, Conn.) administration at a rate of 0.14 mg/kg/min for 4 minutes. Three minutes after completion of the infusion, 2.0 to 2.5 mCi of intravenous thallium 201 (Du Pont Diagnostic Imaging Div., Wilmington, Del.) was injected. Patients were carefully monitored for the development of side effects, including chest pain or ECG changes. Aminophylline was administered intravenously to reverse any discomforting symptoms or ST depression greater than 1 mm. Serial planar myocardial images were collected initially (5 minutes after thallium) and 180 minutes later, in the anterior, 45-degree left anterior oblique, and left lateral positions. Tracer activity in each of these segments was then graded quantitatively, as previously described by experienced nuclear cardiologists who had no knowledge of the patients' clinical history, t° Segmental perfusion defects that did not fill in on

DTS predicts perioperative and late survival 973

delayed images were called fixed defects (infarcts), whereas those that did fill in (partially or completely) were termed redistribution (ischemia). The number and type of abnormal segments, as well as the development of ST segment depression or chest pain during the scan, was recorded. Delayed reinjection of thallium and repeat imaging were not used during this study. Follow-up data were obtained by one of three vascular surgeons who evaluated each patient every 6 to 12 months after operation, In addition, patients, their families, and physicians were questioned for the occurrence of study end points. Nonfatal myocardial infarctions were confirmed by the ECG and enzyme criteria mentioned above. Fatal cardiac events were confirmed by hospital records, autopsy findings, and death certificates. Mean follow-up was 30.1 months. Only five patients were lost to follow-up or could not have their study end point confirmed. All results were expressed as the mean + 1 standard deviation. A p value of < 0.05 was considered statistically significant in all analyses. A comparison of the incidence of clinical and scan variables among the different patient subgroups was made by use of a Pearson chi square (BMDP4F; Biomedical Data Package, University of California Press, Berkeley, Calif.). These analyses were not used to generate statistical predictors but rather are presented only for clinical interest. Stepwise logistic regression analysis (BMDPLR) was used to determine the statistical value in the prediction of perioperative events (cardiac death or myocardial infarction) for all clinical (Table I) and scan (Table II) variables. For the determination of the predictive value of these variables for late cardiac events, the Cox proportional hazards model (BMDP2L) was used. In addition, life-table analysis by use of Kaplan Meier curves (BMDP1L) for cardiac events were used to assess the value of various scan parameters on event-free survival, and differences in event rates were compared with the Mantel-Breslow statistic. RESULTS

The distribution of clinical risk factors among the three operative groups and total population is displayed in Table I. The distribution was essentially similar, except that the frequency of diabetes was substantially higher for patients undergoing an infrainguinal reconstruction. Also, patients having aortobifemoral bypass were more likely to be younger, and there were more men in the abdominal aortic aneurysm group. The DTS parameters are

Journal of VASCULAR SURGERY

974 Cutler, Hendel, and Leppo

TaMe I. Clinical comparison of operative groups Infrainguinal reconstruction (N = 87)

Abdominal aortic aneurysm (N = 108)

Aortobifkmoral bypass (N = 67)

All (N = 262)

No. (%)

No. (%)

No. (%)

No. (%)

69 -+ 8 36 (41) 50 (57) 35 (40) p < 0.001 48 (55) 17 (20) 31 (36) 16 (18) 28 (32)

69 _+ 9 50 (46) 84 (78) p < 0.01 7 (7) 62 (57) 18 (17) 35 (32) 4 (4) 27 (25)

62 -+ 10 p < 0.05 11 (16) p < 0.01 36 (54) 9 (13) 40 (60) 13 (19) 18 (27) 4 (6) 14 (21)

67 -+ 10 97 (37) 170 (65) 51 (20) 150 (57) 48 (18) 84 (32) 24 (9) 69 (26)

Clinical parameter

Mean age Age > 70 yr Male Diabetes Hypertensive Angina Previous MI CHF Q wave

214/, Myocardial infarction; CHF, congestive heart failure. Q wave, Q wave -> 1 mm on resting preoperative ECG.

Table II. Dipyridamole-thallium scintigraphic findings Infrainguinal reconstruction ~ = 87)

Abdominal aortic - aneurysm ~ = 108)

Aortobifemoral bypass ~ = 67)

All (N = 262)

Scan parameter

No. (%)

No. (%)

NO. (%)

No. (%)

Abnormal scan Fixed defect Redistribution Redistribution ->2 segments Fixed ->2 segments ST depression Chest pain

61 (70) 47 (54) 45 (52) 17 (20) 22 (25) 8 (9) 7 (8)

79 56 55 18 27 10 7

43 (64) 29 (43) 32 (48) 16 (24) 13 (19) 5 (8) 3 (5)

183 (70) 132 (50) 132 (50) 51 (20) 62 (24) 23 (9) 17 (7)

(73) (52) (51) (17) (25) (9) (7)

ST depression, ST segment ECG depression after dipyridamole infusion; Chestpain, chest pain after dipyridamole infusion.

shown in Table II. Abnormal scans were noted in 70% of all patients before operation, and fixed or transient defects were equally distributed. The overall frequency of scan abnormalities was similar between the three operative groups. Events during the perioperative phase are shown in Table III, A, and long-term follow-up events, excluding those patients who died in the perioperafive period, are displayed in Table III, B. During the perioperative period, a cardiac event was more likely to be a nonfatal myocardial infarction (18 of 24, 75%), whereas during late follow-up cardiac events were usually fatal (21 of 33, 64%). Patients tradergoing infrainguinal bypass grafts had the highest risk (14%) of sustaining a postoperative myocardial infarction. The risk of late death did not differ among these groups. Logistic regression analysis was used to evaluate the prognostic significance of six clinical and seven scintigraphic factors in predicting perioperative cardiac events (Table IV). The values displayed are from the final step of the model. The presence of redistribution on the preoperative scan was found to be the strongest predictor, with a relative risk value of 6.

Once thallium redistribution is entered into the model, only the presence of ST depression and diabetes offer any significant improvement in prognostic utility above that of redistribution alone. Other, less powerful independent predictors were redistribution greater than 2 segments, abnormal scan, redistribution greater than 1 segment, and the presence of persistent defects. In a separate analysis of patients with abnormal scans, the presence of a moderate-sized area of redistribution was the best predictor (p < 0.001). Of the clinical risk factors, only diabetes and age greater than 70 years achieved minimal significance at the initial univariate step. In the analysis of late cardiac events, 13 perioperative deaths and 18 nonfatal myocardial infarctions were excluded. A Cox proportional hazards model (Table V) was used to evaluate the value of these clinical and scan parameters and showed that the presence of a fixed defect was the most powerful predictor of a late cardiac event (p < 0.0000). Once the presence of a fixed defect was entered into the model, only a history of congestive heart failure was found to offer any statistical improvement (p < 0.01 at step 1). At the initial univariate step other less

Volume 15 Number 6 June 1992

D T S predicts perioperative and late survival

975

Table III, A. Perioperative events Infrainguinal reconstruction (N = 87)

Abdominal aortic aneurysm (N = 108)

Aortobifemoral bypass (N = 67)

All ~ = 262)

Event

No. (%)

No. (%)

No. (%)

No. (%)

Cardiac death Fatal MI Pump failure/arrhythmia Nonfatal MI Noncardiac-related death

0 1 (1) 12 (14) p < 0.01 2 (2)

1 (1) 3 (3) 5 (5) 2 (2)

0 (0) 1 (1) 1 (2) 3 (5)

6 (2) 1 (0.4) 5 (2) 18 (7) 7 (3)

Table III, B. Late events (excluding perioperative deaths), Infrainguinal reconstruction ~ = 84)

Abdominal a o r t i c aneurysm(N = 102)

Aortobifemoralbypass (N = 63)

All (N = 249)

Event

No. (%)

No. (%)

No. (%)

No. (%)

Cardiac death Fatal MI Nonfatal MI Noncardiac-related death

9 (11) 5 (6) 4 (5)

9 (9) 6 (6) 1 (1)

3 (5) 1 (2) 2 (3)

powerful predictors were identified such as abnormal scan, fixed defect of 1 or 2 segments, Q wave on preoperative ECG, history of previous infarction, diabetes, angina, and a nonfatal postoperative myocardialinfarction. However, none of these predictors, including survivors ofperioperative infarction, added any statistical improvement to the presence of a fixed defect on the preoperative scan or a history of congestive heart failure. It is surprising to note that redistribution that has been demonstrated to be a powerful predictor of perioperative events in many prior studies was not useful. When the analysis was restricted to those patients with an abnormal scan outcome, only the presence of fixed defects greater than 1 or 2 segments were predictive of a late event (p = 0.006). The results of fife-table analysis of event-free survival (absence of cardiac death or myocardial infarction) are shown in Fig. 1, Table VI, and include both perioperative (0 time) as well as late events. Therefore this figure shows the event rate for all patients at the point of their decision to go to operation. If perioperative events are excluded, this analysis still results in a significant distribution on the basis of scan results. Patients with redistribution and combined scan detects have an initial cluster of perioperative events, 75% of which are nonfatal myocardial infarctions. Subsequently, there is very little attrition during the follow-up period in those patients having only redistribution. By contrast, patients with fixed defects have very httle periopera-

21 21 12 7

(8) (8) (5) (3)

Table IV. Logistic regression analysis (perioperative cardiac events)

Predictor

Chi square

p value

Relative risk +-95% confidence interval

Any redistribution ST depression Diabetes

15 6.1 4.6

0.0001 0.0015 0.0214

6 + 2.8 4 -- 2.5 3 +- 2.1

ST depression, ST depression after dipyridamole iNecfion. Values at final model (step 3).

tive morbidity but then have a progressive decline in event-free survival, of which 64% was due to fatal myocardial infarctions (p < 0.0001). A similar late event rate is noted in those patients having combined defects, which is attributable to the fixed component, since the late event rate is exceedingly low in patients with only redistribution. Consequently, the presence of a fixed defect on a preoperative DTS and, to a lesser extent, a history of congestive heart failure were the most powerful predictors of late cardiac morbidity and death after major vascular surgery. Moreover, a quantitative relationship exists between the size of the defect and event-free survival. Although it is widely believed that operations on the abdominal aorta carry a higher risk of cardiac complications than do peripheral procedures, our data favor the converse conclusion. The risk of a cardiac event was greater both in the perioperative period and long term for patients having femo-

976

j'ournal of VASCULAR SURGERY"

Cutler,Hendel, and Leppo

100

i oo.:,.,

......

80-

-'~'r.'~.

...........

~..........

"i

"L"L. ~

(1)

|..~.,_.

60-

:..... L . . , . - . I

~o~

Uc~)

uJ

40-

Normal

20-

----

Redistribution

....

Both

.....

,,,,o,,,,o,,oo,o,oo.,,

....... Fixed 0

o

4'8

2;.

6'0

72

Months Fig. 1. Kaplan Meier survival curves, comparing cardiac event-free survival with the result of preoperative dipyridamole-thalfium scanp < 0.0001. When perioperative events are excluded p < 0.001.

Table V. Cox proportional hazards model (late cardiac events)

Predictor

Chi square

p value

Relative risk +95% confldenge interval

Any fixeddefect CHF

30.8 8.0

0.0000 0.005

10.2 _+ 3.8 3.5 ± 2.4

Values at finalmodel (step 2).

parison to an actuarial survival curve for an age- and sex-matched population, n Survival at the time of mean follow-up (31 months) was 97.2% for patients with a normal scan result, compared with 90.9% for the general population. Only five patients in this entire population had a late revascularization procedure (aortocoronary bypass or angioplasty), and one nonfatal infarction occurred. No separate analysis was performed on this small subgroup. DISCUSSION

ropopliteal or femorotibial bypass grafts than for procedures on the abdominal aorta. The combined perioperative and late event rate was 29% for infrainguinal procedures, 19% for abdominal aortic aneurysm, and 7.5% for aortobifemoral bypass (p = 0.012). Life-table analysis (data not shown) of these three procedures showed that event-free survival (including perioperative deaths) at 5 years was 55% for the infrainguinal group, 75% for abdominal aortic aneurysm (p < 0.02), and 85% for patients undergoing aortobifemoral bypass grafts (p < 0.01). When perioperative events were excluded from the analysis, the differences between the three groups were not significant. Perioperative and late event-free survival were best among patients who had neither fixed defects nor redistribution (normal) on their preoperative scan. None of the 79 patients with normal scan outcomes had a cardiac event after operation, and only two events occurred during late follow-up, both of which were fatal myocardial infarctions, permitting com-

Logistic regression analysis of a variety of clinical risk factors and scan parameters showed that the presence of redistribution on a preoperative scan was the strongest predictor of perioperative cardiac morbidity and death, with a relative risk of 6. Other important predictors were the development of ST segment depression after dipyridamole injection (relative risk, 4) and a history of diabetes (relative risk, 3). Among patients with abnormal findings on their scan, logistic regression selected those scans with two or more segments of redistribution as the most significant factor. Fixed defects were not predictive. Previous studies have found that the perioperative cardiac event rate for patients with DTS redistribution ranged from 5% to 50%. 2'4'7'8'10'12-14 Although none of these studies found predictive significance for a fixed defect, McEnroe et al.6 noted that seven of 15 patients undergoing aortic aneurysm surgery with fixed defects had a postoperative event. All investigators have observed that the cardiac risk for patients with a normal scan to be no more than

Volume 15 Number 6 June 1992

DTS predicts perioperative and late survival 977

Table VI. Preoperative dipyridamole-thallium scan and cardiac event-free survival 0 mo

Scan result

No.

Normal Redistribution Fixed Both

79 51 51 81

12 mo

Cumulative survival 1.0 0.882 0.941 0.827

-+ -+ -+ -+

0 0.045 0.033 0.042

No. 70 39 31 55

Cumulative survival 0.987 0.882 0.883 0.798

-+ 0.013 +_ 0.045 --- 0.058 -+ 0.045

24 mo

No. 52 30 19 35

Cumulative survival 0.973 0.882 0.793 0.694

_+ 0.019 + 0.045 + 0.063 + 0.056

36 mo

No. 40 20 12 26

Cumulative survival 0.972 0.882 0.691 0.694

_+ 0.019 + 0.045 + 0.087 + 0.056

48 mo

No. 21 12 5 12

Cumulative survival 0.972 0.823 0.553 0.601

+ 0.019 _+ 0.071 _+ 0.142 _+ 0.078

No., N u m b e r at risk. Cumulative survival is _+ standard error.

5%. In the present study, there were no perioperative events among 79 patients with normal scan outcomes. The observation that a quantitative relationship may exist between the number of segments of redistribution and the risk of a postoperative cardiac event is in accord with three recent reports. Levenson et al)6 noted that the risk of a postoperative event was 38%, with 4 or greater segments of redistribution compared with only 12% with 3 or fewer segments. Furthermore, when two or three coronary territories were involved, the risk was 43% compared with 13% in patients with redistribution in only one area. In a second study, of 101 patients with diabetes Lane et al)7 found that as the number of segments of redistribution increased from 2 to 5, the positive predictive value of DTS increased from 18% to 44%, although sensitivity declined. In addition, the presence of redistribution in the territory of the left anterior descending artery was an added risk factor. Finally, Lette et al.7 have developed semiquantitative scintigraphic indexes to grade the severity and extent of redistribution on preoperative DTS to stratify operafive risk. Using their scheme, they observed a cardiac event rate of 5% for an intermediate and 85% for a high-risk scan. It therefore appears that the risk of a perioperative cardiac event after vascular surgery is related not only to the presence of redistribution but to the total area of redistribution and its presence in the anatomic territories of multiple coronary arteries. Despite the fact that Leppo et al.18 initially reported the use of DTS to predict cardiac events in patients surviving myocardial infarction, the most popular use of DTS has been for the preoperative cardiac evaluation of patients undergoing vascular surgery. In the study by Leppo et al. of patients after infarction with scan redistribution, 16% died, 14% had reinfarction, and 57% had further ischemic events during an average follow-up of 19 months. Younis et al.19,20 in twO separate studies and Hendel et al.21 later confirmed that among a variety of clinical

and scan parameters, redistribution, and to a lesser extent, clinical evidence of reduced left ventricular function were the most important predictors of event-free survival in patients with ischemic heart disease. It is interesting to note that in the study by Hendel et al., a persistent defect was a significant univariate (p = 0.0003) for late cardiac events. The present study found that a fixed defect on the preoperative scan was the best predictor of late cardiac events (p < 0.0000). Furthermore, a quantitative relationship existed between the number of fixed segments and cardiac risk. However, it should also be noted that referring physicians were aware of the presence of thallium redistribution in their patients and may have implemented medical therapy that reduced the long-term cardiac event rate in this subgroup. It is widely accepted that redistribution occurs in areas of ischemic myocardium that may become symptomatic in the form of angina or can progress to infarction in response to the increased myocardial oxygen demands of a vascular operation and anesthesia. The data from perioperative and postinfarction studies indicate that nonfatal cardiac events are far more common than cardiac death, ranging from 50% to 71% .6-8,9,16,17On the other hand, fixed defects that are more likely to be the consequence of previous myocardial infarction and may signal impairment of ventricular function seem to correlate best with late fatal cardiac events. Support for this theory comes from the observation in this study that 64% of late cardiac events were fatal myocardial infarction compared with 25% in the perioperative period. Furthermore, logistic regression analysis selected a history of congestive heart failure, indicative of impaired ventricular function, as the most important clinical risk factor for late cardiac death (p < 0.0001). In a similar manner congestive heart failure and reduced ejection fraction were noted to be important in predicting late survival by both Hendel et al.21 and Younis et al.19,20

978

Cutler,Hendel, and Leppo

In a longitudinal study of 111 patients with peripheral vascular disease who had a preoperative DTS, and were monitored for a mean of 18 months, Younis et al. 22 found redistribution to be the best predictor of both early and late cardiac events (p < 0.001). When cardiac catheterization data were included in the regression analysis (N = 38), global left ventricular ejection became the most important predictor, and fixed defects were close to significant (p = 0.06) for late events. However, it is of interest that their late event analysis did not use a Cox regression, included perioperative events as a positive end point, and did not differentiate late cardiac death from myocardial infarction. Therefore comparison with our data is difficult. In addition, the patients of Younis et al. were monitored for a mean of 18 months, which may not have been long enough to overcome the initial effect of redistribution-related perioperative cardiac events. Analysis of the eventfree survival curve for all patients in our study (Fig. 1, Table VI) does not show a significant difference between redistribution and fixed defects until approxamately 30 months, nearly twice as long as the mean follow-up in the study by Younis et al. Therefore it appears that clinical risk factors and scan parameters that reflect reduced left ventricular fraction, namely a history of congestive heart failure and multiple fixed defects, correlate most strongly with relatively late cardiac events after peripheral vascular operations. Perhaps the most striking finding in this study was the low incidence of cardiac events among patients with a normal scan outcome. There were no perioperative and only two late events among 79 patients with a normal scan outcome. The low perioperative risk with a normal scan result has been observed by most authors, but the event-free survival of 97.5% (Fig. 1, Table VI) during a follow-up that extended to 5 years, actually exceeds the actuarial survival for an age- and sex-matched population. The improved survival, even with the added risk of a major vascular operation, suggests that the incidence of significant CAD in this group is less than in a comparable population without peripheral vascular disease. Previous studies of DTS in patients with peripheral vascular disease have been l~mited to patients undergoing aortic surgery, on the assumption that aortic operations carry the greatest cardiac risk. 1,2,s,6,9,2s,2~ Other studies have included a variety of vascular procedures, ~ but none has analyzed the .

~References 3, 4, 7, 8, 10, 12, 13, 14, 16, 17

Journal of VASCULAR SURGERY

data by operative category, as in the present study. Our data show that patients undergoing a femoropopliteal or femorotibial bypass graft have the highest risk of combined perioperative and late cardiac events (29%) compared with patients undergoing aortic aneurysm (19%) or aortobifemoral bypass grafts (7.5 %). Life-table analysis of these three procedures at the time of mean follow-up (31 months) showed that event-free survival for infrainguinal reconstruction was significantly less than for either aortic aneurysm (p < 0.02) or aortobifemoral bypass (p < 0.01). It is surprising that survival was best after aortobifemoral reconstruction, probably reflecting selection bias. Since the results of the scan were available to the surgeon, cardiologist, and anesthesiologist it is likely that patients with aortoiliac occlusive disease who had markedly positive scan outcomes underwent an alternative form of therapy such as percutaneous angioplasty, extraanatomic bypass, or conservative management. The lower incidence of abnormal outcomes on scans in the aortobifemoral group compared with the aortic aneurysm and infrainguinal groups (Table II) favors this explanation. It should also be noted that the incidence of diabetes in patients undergoing an infrainguinal reconstruction was more than twice that of the other two groups, which may account for a greater frequency and severity of associated CAD. Last, it has been suggested that infrainguinal occlusive disease in itself may serve as a marker for three-vessel coronary disease. 2s Whereas the presence of redistribution on a preoperative dipyridamole-thallium scan has been extensively demonstrated to predict perioperative cardiac events, the present study has shown that over time, fixed defects provide better prognostic utility than redistribution. Moreover, a quantitative relationship appears to exist between the number of fixed defects and long-term survival. In addition, the predictive value of fixed defects was observed in all three subgroups of patients who underwent infrainguinal, aortic aneurysm, and aortoiliac reconstruction. Although fixed defects have not previously been reported to have prognostic value in patients undergoing vascular surgery, our data suggest it to be a major factor in late follow-up especially when combined with clinical evidence of impaired left ventricular function. Such findings should be carefially considered when choosing among the therapeutic alternatives for patients with peripheral vascular disease. Recent reports by Rocco et al. 26 and Dilsizian et al) 7 have observed that 31% to 49% of fixed defects

Volume 15 Number 6 June 1992

o n the 3 - h o u r t h a l l i u m scan i m p r o v e d after the reinjection o f t h a l l i u m a n d a t h i r d scan. A l t h o u g h o u r l a b o r a t o r y n o w uses s e c o n d a r y injection a n d d e l a y e d i m a g i n g o n all patients w i t h u n e x p e c t e d fixed defects, this was n o t the practice at t h e t i m e t h e d a t a were collected for fills study. W e believe t h a t the e x t e n d e d p r o t o c o l will refine the utility o f p r e o p e r a t i v e D T S screening b u t will n o t significantly alter the conclusions o f the p r e s e n t investigation.

DTS predicts perioperative and late survival 979

14.

15.

16.

We thank Robert A. Lew, PhD (statistics) who performed the statisfcal calculations and Laury Allen for manuscript preparation. 17. REFERENCES 1. Sttawn DJ, Guernsey JM. Dipyridamole thallium scanning in the evaluation of coronary artery disease in elective abdominal aortic surgery. Arch Surg 1991;126:880-4. 2. Cutler BS, Leppo JA. Dipyridamole thallium 201 scintigraphy to detect coronary artery disease before abdominal aortic surgery. 1 VASCSURG 1987;5:91-100. 3. Fletcher JP, Antico VF, Gruenewald S, Kershw LZ. Dipyridamole-thaUium scan for screening of coronary artery disease prior to vascular surgery. J Cardiovasc Surg (Totino) 1988;29:666-9. 4. Sachs RN, Tellier P, Larmignat P, et al. Assessment by dipyridamole-thallium-201 myocardial scintigraphy of coronary risk before peripheral vascular surgery. Surgery 1988; 103:584-7. 5. Gouny P, Bertrand M, Coriat P, Kieffer E. Perioperative cardiac complications of surgical repair of infrarenal aortic aneurysms. Ann Vasc Surg 1989;3:328-34. 6. McEnroe CS, O'Donneil TF Jr, Yeager A, Konstam M, Mackey WC. Comparison of ejection fraction and Goldman risk factor analysis to dipyridamole-thalfium 201 studies in the evaluation of cardiac morbidity after aortic aneurysm surgery. J VASCSutm 1990;11:497-504. 7. Lette J, Waters D II, Lassonde J, et al. Multivariate clinical models and quantitative dipyridamole-thallium imaging to predict cardiac morbidity and death after vascular reconstruction. J VASCSURG 1991;14:160-9. 8. Eagle KA, Singer DE, Brewster DC, Darling RC, Mulley AG, Boucher CA. Dipyridamole-thailium scanning in patients undergoing vascular surgery. Optimizing preoperative evaluation of cardiac risk. JAMA 1987;257:2185-9. 9. Eagle KA, Coley CM, Newel] [[B,et al. Combining clinical and thallium data optimizes preoperative assessment of cardiac risk before major vascular surgery. Ann Intern Med 1989;110: 859-66. 10. Leppo J, Plaja J, Gionet M, Tumolo J, Paraskos JA, Cutler BS. Noninvasive evaluation of cardiac risk before elective vascular surgery. J Am Coil Cardiol 1987;9:269-76. 11. U.S. Bureau of the Census. Statistical abstract of the United States, 1990. 110th Edition. Table 106. United States Government Printing Office, Washington, DC, 1990:12. 12. Boucher CA, Brewster DC, Darling RC, Okada RD, Strauss HW, Pohost GM. Determination of cardiac risk by dipyridamole-thallium imaging before peripheral vascular surgery. N Engl J Med 1985;312:389-94. 13. Brewster DC, Okada RD, Strauss HW, Abbott WM, Darling RC, Boucher CA. Selection of patients for preoperative

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26.

27.

coronary angiography: use of dipyridamole-stress-thallium myocardial imaging. J VASCSURG 1985;2:504-10. Mangano DT, London MJ, Tuban JF, et al. Dipyridamole thallium-201 scintigraphy as a preoperative screening test. A reexamination of its predictive potential. Circulation 1991; 84:493-502. Lette J, Waters DI, Lassondc 1, et al. Postoperative myocardial infarction and cardiac death. Predictive value of dipyridamolethallium imaging and five clinical scoring systems based on multifactorial analysis. Arin Surg 1990;211:84-90. Levinson JR, Boucer CA, Coley CM, Guiney TE, Strauss HW, Eagle KA. Usefulness of semiquantitative analysis of dipyridamole-thallium-201 redistribution for improving risk stratification before vascular surgery. Am J Cardiol 1990;66: 406-10. Lane SE, Lewis SM, Pippin lJ, et al. Predictive value of quantitative dipyridamole-thallium scintigraphy in assessing cardiovascular risk after vascular surgery in diabetes meRitus. Am J Cardiol 1989i64:1275-9. Leppo JA, O'Brien J, Rothendler JA, Getchell JD, Lee VW. Dipyridamole-thallittm-201 scintigtaphy in the prediction of future cardiac events after acute myocardial infarction. N Engl J Med 1984;310:1014-8. Younis LT, Byers S , Shaw L, Barth G, Goodgold H, Chaitman BR. Prognostic value of intravenous dipyridamole thallium scintigraphy after an acute myocardial ischemic event. Am J Cardiol 1989;64:161-6. Younis LT, Byers S, Shaw L, Barth G, Goodgold H, Chaitman BR. Prognostic importance of silent myocardial ischemia detected by intravenous dipytidamole-thallium myocardial imaging in asymptomatic patients with coronary artery disease. 1 Am Coil Cardiol 1989;14:1635-41. Hendel RC, Layden JJ, Leppo JA. Prognostic value of dipyridamolethallium scintigraphy for evaluation ofischemic heart disease. J Am Col] Cardiol 1990;15:109-16. Younis LT, Aguirre F, Byers S, et al. Perioperative and long-term prognostic value of intravenous dipyridamole thallium scintigraphy in patients with peripheral vascular disease. Am Heart J 1990;119:1287-92. Grant RP, Morgan C, Page MS, Maim DN, Huckel V, Jenkius LC. Dipyridamole-thailium myocardial scanning in the preoperative assessment of patients undergoing abdominal aortic aneurysmectomy. Can J Anaesth 1990;37:409-15. McPhail NV, Ruddy TD, Calvin [[E, Davies RA, Barber GG. A comparison of dipyridamole-thailium imaging and exercise testing in the prediction of postoperative cardiac complications in patients requiting arterial reconstruction. J VASC SURG 1989;10:51-6. Kaliero KS, Bergqvist D, Cederholm C, Jonsson K, Olsson PO, Takolander R. Arteriosclerosis in popliteal artery trifurcation as a predictor for myocardial infarction after arterial reconstructive operation. Surg Gynecol Obstet 1984;159: 133-8. Rocco TP, Dilsizian V, McKusick KA, Fischman AJ, Boucher CA, Strauss HW. Comparison of thallium redistribution with rest "reinjection" imaging for the detection of viable myocardium. Am J Cardiol 1990;66:158-63. Dilsizian V, Rocco TP, Freedman NMT, Leon MB, Bonow RO. Enhanced detection of ischemic but viable myocardium by the reinjection of thallium after stress-redistribution imaging. N Engl J Med 1990;323:141-6.

Submitted Oct. 4, 1991; Jan. 28, 1992.

980

Cutler,Hendel, and Leppo

Journal of VASCULAR SURGERY

DISCUSSION

Dr. Richard Cambria: (Boston, Mass.). The present study is the latest chapter in a series of reports from Cutler et al. at the University of Massachusetts dealing with the utility of the DTS in patients undergoing vascular surgery. More than 250 patients undergoing aortic and infrainguinal operations were routinely evaluated with preoperative scans and monitored for perioperative and late cardiac events, with a mean follow-up of nearly 3 years. With respect to perioperative cardiac ischemic events, their findings mirror a number of recent reports insofar as first, redistribution on DTS was associated with perioperative cardiac events, yet the test suffers from both poor specificity and a low positive predictive value. For example, redistribution on DTS was noted in 50% of all their patients before surgery, yet rates of perioperative myocardial infarction were very low, especially in patients undergoing aortic surgery. Second, rates of perioperative nonfatal myocardial infarction for infrainguinal revascularization equals or (as in this study) exceeds that for aortic surgery. The principal focus of this report is the relationship of dipyridamole-thallium scans to late survival in patients undergoing vascular surgery. Here the authors, somewhat surprisingly, found no significant relationship between redistribution and late events, although it is important to note that the clustering of events in the perioperative period, that is, those with redistribution, were excluded from late survival figures. In addition, our own data have suggested that redistribution is predictive of late events. In the present study the presence of so-called fixed defects, that is myocardial scars, were predicted in a quantitative manner for late and usually fatal cardiac events. Among clinical variables examined, a history of heart failure and operation for infrainguinal disease also correlated with excess late deaths. Perhaps we have come full circle and should again be including an assessment of ejection fraction in the overall cardiac evaluation before vascular surgery. We agree that the capacity for quantitative information is perhaps the most appealing aspect of the dipyridamolethallium scan. In our unit coronary angiography and/or invasive treatment of CAD is presently restricted to patients with mukiple zones of redistribution, and, as mentioned by Dr. Cutler, these are generally patients with evidence of triple vessel disease or so-called global ischemia. This leads me to my first question. I ask the authors, in their present practice, what is the rate of cardiac catheterization before vas~lar surgery? To focus a moment on the infrainguinal group, we agree that these represent the patients with most advanced disease, and our data have also identified operation for infrainguinal disease as an independent predictor of late cardiac events. I have a question about the 10 patients who underwent primary amputations. If we include these in the infrainguinal group, that is, 10 of 97 patients or a 10% rate of primary amputation rather than revascularization, this

seems somewhat high to us. Were these primary amputations carried out because of undue cardiac risk, or were there other clinical factors involved? We should not lose sight of the fact that the previous work from both our own group and the group at the University of Massachusetts is intended to help the practicing vascular surgeon in the selection of patients for these preoperative tests. We currently apply the dipyridamole-thallium scan in a selective, not routine, fashion on the basis of the presence or absence of certain clinical markers of CAD. Recently we validated this concept and approximately one third of our patients before aortic surgery undergo scanning, with some 10% then having coronary angiography and percutaneous transluminal coronary angiography; with such selective evaluation and treatment, overall current rates of cardiac mortality and nonfatal myocardial infarction are in the 2% range. Will you outline your current use of the dipyridamole-thallium scan in patients before vascular surgery? Dr. Bruce Cutler. Your first question concerned the further evaluation of patients with abnormal dipyridamolethallium scan outcomes and the frequency of cardiac catheterization. In this study 26 of 262 patients underwent cardiac catheterization. Seven of these had preliminary coronary revascularization, without subsequent cardiac morbidity or deaths. Eight of the other 19 who underwent cardiac catheterization and vascular reconstruction without coronary revascularization had a cardiac event. Since the patients who had preliminary coronary revascularization did so well, why did we not recommend coronary bypass to the entire group? We would have, but unfortunately, most of the 19 patients either had diffuse coronary disease or multiple lesions of borderline hemodynamic significance that were not amenable to either coronary angioplasty or bypass surgery. Dr. Cambria noted that 10 patients underwent amputation, which is a high rate within a group of 97 infrainguinal reconstructions. Five of the 10 patients having amputations were major, and the rest were at the transmetatarsal level Because this study was restricted to patients having a preoperative DTS before either aortic or infrainguinal operation, patients who had a primary amputation were exluded. I do not have the specific indications for amputation available to me, at present. Finally, Dr. Cambria has challenged me to resolve the controversy between selective and routine DTS before vascular surgery. The results of our study cannot decide this issue. Since the incidence and severity of coronary artery disease in patients undergoing vascular operations varies between hospitals, and because anesthesiologists and cardiologists have differing preferences for preoperative evaluation of patients having vascular surgery, the use of DTS can be expected to vary from institution to institution. I would suggest that each vascular surgeon review the incidence of postoperative cardiac events in his own

Volume 15 Number 6 June 1992

hospital and if that figure is 8% to 10% or more then he should consider routine DTS screening. If the incidence is significantly less, then selective screening on the basis of clinical risk factors such as those described by the Massachusetts General Hospital group is appropriate. Dr. Frank Pomposelli (Boston, Mass.). Dr. Cutler, if I understood your presentation correctly, your perioperatire infrainguinal reconstruction cardiac event rate including deaths, was the highest in all three groups. This stands somewhat in contrast with our own recent experience in infrainguinal reconstructions in a larger (90%) diabetic population when our perioperative cardiac mortality rate has been between 0.5% and 3%, with about twice that number for nonfatal perioperative myocardial infarction. Because of this low perioperative mortality rate, we have not routinely used dipyridamole scanning in this group. Moreover, we have found that many diabetic patients are ~symptomatic in spite of 75% having positive scan results. In addition, many of these patients cannot wait to have their cardiac disease corrected because of the urgency of the need for infrainguinal reconstruction. As a result, we have concentrated our efforts, more on intraoperative and perioperative management. We routinely use anesthesiologists experienced in cardiac anesthesia and place balloontipped pulmonary artery catheters and arterial lines in all patients undergoing infrainguinal reconstruction regardless of preoperative cardiac status. Do you do this and do you think it is valuable? Dr. Bruce Cutler. Dr. Pomposelli mentioned the dilemma of the diabetic patient with a positive DTS outcome and need for urgent infrainguinal revascularization. Our study has shown that this subgroup has a 27% risk of perioperative cardiac events. Consequently, if you conclude that a patient "cannot wait to have his cardiac disease corrected..." then, on the basis of our data, we would recommend choosing an anesthetic technique with the least myocardial depression and using intracardiac monitoring. Dr. Thomas O'DonneU (Boston, Mass.). I have a question about the prognostic significance of a fixed defect. As you know, our group has had different results than yours concerning the risk of a fixed defect on preoperative scan for a subsequent perioperative cardiac event. We found that fixed defects were associated with an appreciable incidence of adverse cardiac events. We came to the conclusion that perhaps all these defects were not fixed, but rather a rim of redistribution surrounded the defect which

DTS predicts perioperative and late survival 981

reperfused quite late. Subsequent papers from our cardiology group showed that approximately one third of patients with fixed defects will have a rim of redistribution around the defect on late reinjection. Since your fixed defects were the only factors predictive for long-term cardiac morbidity, did you use the reinjection technique to sort out true fixed defects from late redistribution? Maybe all the defects were not fixed, and some had a rim of redistribution. The late redistribution scans may account for the adverse prognostic significance of a "fixed defect." Dr. Cutler. Data gathering for this study ended in December 1990 before publication of papers that demonstrated the advantage of delayed thallium injections in defining fixed defects. We now use secondary injection and delayed imaging on all patients with unexpected fixed defects. We believe that this extended protocol will refine the utility of preoperative DTS screening but will not significantly alter the conclusions of the present study. Dr. David Brewster (Boston, Mass.). Dr. Cutler, I am interested in your thoughts about the implications of a fixed defect in the long-term management of the patient. Are these patients at all amenable to later revascularization? So often, if a patient survives their aortic or peripheral vascular operation, I think some of the impetus for cardiac evaluation and ongoing care is lost. Your results suggest the possibility that a concept of "reverse staging" might be applicable, where, after successful vascular surgery, perhaps later coronary revascularization might be indicated. Is this feasible in this subgroup of patients? Dr. Cutler: In the past, a peripheral vascular operation has been regarded as a "survival test" of sorts. Our data indicate that patients who survive an aortic or infrainguinal reconstruction, who have multiple fixed defects on their preoperative DTS are at an increased risk for late cardi"ac events and therefore deserve close cardiologic follow-up. Perhaps the threshold for cardiac catheterization should be lower in this group, as you have suggested. Dr. Michael H u m e : (Boston, Mass.). I have one final question. The patient undergoing carotid surgery does concern the anesthesiologist very much because of labile blood pressure during the procedure. Do you do any less of a workup? Dr. Cutler. We do not perform preoperative dipyridamole-thallium scans routinely before carotid surgery. Instead, we use it selectively on patients with known or suspected CAD on the basis of history or ECG findings.